The pathogenesis of the chronic fatigue syndrome ( S) includes severe and debilitating fatigue, orthostatic intolerance, and the disruption of autonomic, hematological, and cardiovascular function. Plasma volume expansion is associated with a reduction or resolution of orthostatic hypotensive symptoms in some but not all CFS patients. Preliminary findings in our lab suggest that: 1) reduced red blood cell (RBC) mass is a critical hematological marker of CFS; and 2) RBC mass expansion improves orihostatic tolerance and fatigue beyond that ascribed to plasma volume expansion alone. However, the physiological mechanisms underlying these treatment effects and the relationship of such mechanisms to individual differences in treatment response have not been elucidated. This proposed 5-year study will extend our previous work in evaluating autonomic, hemodynamic, neuroendocrine, and adrenergic receptor function in individuals with CFS. We will study 90 (of 105 recruited) CDC-defined CFS patients before and after 3-month intervention in a randomized, double-blind, placebo-controlled study of pharmaco-therapy to expand plasma volume compared with combined treatment to expand RBC mass and plasma volume. Therefore, 30 CFS men and women will be randomized to each of three treatment conditions (plasma volume expansion; plasma volume and RBC mass expansion; and placebo) and tested pre- and post-treatment. Echocardiographic evaluation of left ventricular structure and function (left ventricular mass and wall thickness, compliance, and contractility) will be performed to examine whether the diminished cardiac function is a consequence of myocardial origin. Autonomic integrity will be assessed during response to a standardized battery of reflex tests (supine rest, paced respiration, Valsalva maneuver, lying-to standing, and sustained handgrip). Baroreceptor sensitivity and alpha- and beta-adrenoceptor sensitivity will be examined using adrenoceptor pharmacological challenge (phenylephrine, isoproterenol). A 70 degrees head-up tilt (HUT) test combined with beta-adrenergic agonist infusion at 2 microgram/min (and then again at 5 microgram/min if previous test failed to induce a orthostatic hypotension) will be performed to determine orthostatic susceptibility. During these HUT tests noninvasive measurement of parasympathetic cardiac neural input, sympathetic cardiac neural input, catecholamines and measures of hemodynamic function (heart rate, blood pressure, cardiac output, total peripheral resistance) will be derived to assess the autonomic mediation of cardiovascular response to the HUT challenge as a function of treatment. In addition, we will examine the effect of treatment on exertional fatigue in response to the HUT. Then we will examine the relation between the criterion (orthostatic hypotension susceptibility) and the predictors (hemodynamic, autonomic, cardiac structure/function and baroreceptor, alpha-adrenoceptor and beta- adrenoceptor sensitivities) in order to determine the extent to which the predictors are mediating the treatment effects on orthostatic hypotension susceptibility. Therefore, this project will further the investigation of pathophysiological mechanisms in CFS of a deficiency in plasma volume and red blood cell mass as a possible source for the pathophysiology of fatigue and cardiovascular dysfunction by comprehensively examining: a) autonomic and hemodynamic function; b) cardiac structure and function; and c) cardiac and vascular adrenoceptor sensitivity, before and after the pharmacological manipulation of plasma volume and RBC mass expansion.